Meier-Gorlin syndrome 2

Summary

Meier-Gorlin syndrome 2 (MONDO:0013428) is a disease caused by ORC4 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ORC4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 17

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Meier-Gorlin syndrome 2
Mondo ID	MONDO:0013428
OMIM	613800
DOID	DOID:0080513
UMLS	C3151097
MedGen	462447
GARD	0015708
Is cancer (heuristic)	no

Also known as: Meier-Gorlin syndrome 2 · Meier-Gorlin syndrome caused by mutation in ORC4 · Meier-Gorlin syndrome type 2 · MGORS2 · ORC4 Meier-Gorlin syndrome

Data availability: 17 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Meier-Gorlin syndrome › Meier-Gorlin syndrome 2

Related subtypes (9): Meier-Gorlin syndrome 1, Meier-Gorlin syndrome 3, Meier-Gorlin syndrome 4, Meier-Gorlin syndrome 5, Meier-Gorlin syndrome 6, Meier-Gorlin syndrome 7, Meier-Gorlin syndrome 8, Meier-Gorlin syndrome 9, Meier-Gorlin syndrome 10

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

17 retrieved; paginated sample, class counts are floors:

5 pathogenic, 4 uncertain significance, 3 benign, 2 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
30297	NM_181742.3(ORC4):c.(-18+1_-17-1)_(762+1_773-1)del	LOC126806366	Pathogenic	no assertion criteria provided
1299638	NM_181741.4(ORC4):c.623C>G (p.Ser208Ter)	ORC4	Pathogenic	criteria provided, single submitter
211805	NM_181741.4(ORC4):c.1226del (p.Thr409fs)	ORC4	Pathogenic	criteria provided, single submitter
225427	NM_181741.4(ORC4):c.1A>G (p.Met1Val)	ORC4	Pathogenic	criteria provided, single submitter
30295	NM_181741.4(ORC4):c.521A>G (p.Tyr174Cys)	ORC4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30296	NM_181741.4(ORC4):c.870_873dup (p.Ala292fs)	ORC4	Pathogenic	criteria provided, single submitter
1299639	NM_181741.4(ORC4):c.956A>G (p.His319Arg)	ORC4	Likely pathogenic	criteria provided, single submitter
4279004	NM_181741.4(ORC4):c.779del (p.Arg260fs)	ORC4	Likely pathogenic	criteria provided, single submitter
159484	NM_181741.4(ORC4):c.287A>G (p.Gln96Arg)	ORC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
159485	NM_181741.4(ORC4):c.604T>G (p.Leu202Val)	ORC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1384791	NM_181741.4(ORC4):c.1105A>T (p.Lys369Ter)	ORC4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2434515	NM_181741.4(ORC4):c.866G>A (p.Arg289Gln)	ORC4	Uncertain significance	criteria provided, single submitter
4056697	NM_181741.4(ORC4):c.515T>G (p.Leu172Arg)	ORC4	Uncertain significance	criteria provided, single submitter
4279001	NM_181741.4(ORC4):c.-18+64G>A	ORC4	Uncertain significance	criteria provided, single submitter
1247797	NM_181741.4(ORC4):c.-17-5dup	ORC4	Benign	criteria provided, multiple submitters, no conflicts
159483	NM_181741.4(ORC4):c.233A>G (p.Asn78Ser)	ORC4	Benign	criteria provided, multiple submitters, no conflicts
403280	NM_181741.4(ORC4):c.763-9del	ORC4	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ORC4	Definitive	Autosomal recessive	Meier-Gorlin syndrome 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ORC4	Orphanet:2554	Ear-patella-short stature syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ORC4	HGNC:8490	ENSG00000115947	O43929	Origin recognition complex subunit 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ORC4	Origin recognition complex subunit 4	Component of the origin recognition complex (ORC) that binds origins of replication.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ORC4	Enzyme (other)	yes	3.6.4.B8	AAA+_ATPase, ORC4, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
cortical plate	1
oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ORC4	285	ubiquitous	marker	calcaneal tendon, oocyte, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ORC4	1,522

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ORC4	O43929	15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
CDC6 association with the ORC:origin complex	1	1427.5×	0.003	ORC4
E2F-enabled inhibition of pre-replication complex formation	1	1268.9×	0.003	ORC4
Activation of the pre-replicative complex	1	326.3×	0.006	ORC4
Activation of ATR in response to replication stress	1	300.5×	0.006	ORC4
Orc1 removal from chromatin	1	178.4×	0.007	ORC4
Assembly of the ORC complex at the origin of replication	1	165.5×	0.007	ORC4
Assembly of the pre-replicative complex	1	139.3×	0.007	ORC4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
polar body extrusion after meiotic divisions	1	3370.4×	9e-04	ORC4
protein polymerization	1	991.3×	0.002	ORC4
DNA replication initiation	1	624.1×	0.002	ORC4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ORC4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ORC4	3.6.4.B8

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ORC4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ORC4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.